There are thousands of rare genetic diseases that have no approved treatment. Recursion Pharmaceuticals has developed a drug discovery platform that seeks to re-purpose known drugs for the treatment of such diseases. The platform consists of high content immunofluorescent image analysis using machine-learning algorithms to identify relevant and on-target changes induced by both RNAi and various chemicals. This system has been used to identify a phenotype for loss of function of two related genes, RPS19 and RPS10 in multiple human cell types. Mutations in these genes are the primary cause of Diamond Blackfan Anemia, a rare genetic disease with no specific targeted therapy. In this grant, we propose to: develop RPS19 and RPS10 knockout cell lines using CRISPR/Cas9 technology; evaluate knockout cell lines for phenotypes ('phenoprints') using our drug discovery platform; conduct chemical suppressor screens of thousands of known drug candidates to identify those that ameliorate on-target phenoprints associated with loss of RPS19 and RPS10; expand the capabilities of our drug screening platform to enable the use of non-adherent cell lines in our workflow and use the expanded capabilities to confirm the validity of drugs identifie as candidate therapies in CD34+ suspended cell culture models of Diamond Blackfan Anemia. Recursion Pharmaceuticals has the experience, tools, and drive to execute this Phase I SBIR proposal, and to accelerate commercial development of any compounds arising from the project. The proposed study would have significant societal and commercial implications.